Androgen-withdrawal or blockade causes human prostate cancers to die through an orderly cascade of biochemical events called programmed cell death or apoptosis. Unfortunately, after hormone withdrawal, tumors recur containing cells which are capable of androgen-independent growth. We hypothesize that androgen-insensitivity arises, in part, because tumors develop abnormalities in their ability to undergo apoptosis. This inability to undergo apoptosis allows prostate tumor cells to grow in a hormone-independent fashion. This hypothesis is based on preliminary results from our laboratory which demonstrate that (1) prostate tumor cells overexpressing a protein inhibitor of apoptosis, crmA, grow androgen-independently in nude mice although they are normally hormone dependent, and (2) MAP kinase phosphatase (MKP-1), a protein which is overexpressed in human prostate cancer, blocks apoptosis of cultured prostate cancer cells. Thus, the goals for this proposal are to (1) determine in animal and tissue culture models whether MKP-1 overexpression blocks androgen- withdrawal and chemotherapy-induced apoptosis, (2) develop a transgenic mouse model in which MKP-1, an inhibitor of apoptosis, drives prostate cancer development, and (3) examine the enzyme targets and location(s) of action of MKP-1. Information gained from these studies will provide the background and animal models to examine MKP-1 or regulation of apoptosis as a target for antiprostate cancer therapy.